Investigation of Lung Pharmacokinetic of the Novel PDE4 Inhibitor CHF6001 in Preclinical Models: Evaluation of the PreciseInhale Technology

Fioni, Alessandro; Selg, Ewa; Cenacchi, Valentina; Acevedo, Fernando; Brogin, Giandomenico; Gerde, Per; Puccini, Paola

doi:10.1089/jamp.2017.1369

Cited by 25 publications

(14 citation statements)

References 30 publications

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“…The goal for further development is to use the ventilation data, in combination with the signal from the aerosol monitor instrument for active dose control of the aerosol, in the same manner as in the PI (PreciseInhale Ò ) dry powder application. (11) Drying of carrier air was accomplished with 800 mL silica gel in a drying column located upstream of the flow meter. After drying, the carrier air was filtered through a 65 mm filter pad (PARI, Germany) placed at the drying column exit to prevent silica gel dust from entering the exposure line.…”

Section: Methodsmentioning

confidence: 99%

“…1A). (11) Following such phantom exposures, a substance correlation factor can be defined correlating the optical and gravimetric mass flux of aerosol inhaled by the exposure subject. This correlation factor is then used by the software to control the individual exposures in real-time.…”

Section: Fig 1 (A)mentioning

confidence: 99%

“…Exposures are provided to individual animals allowing controlled dosing of smaller lungs based on the actual aerosol concentration and the ventilation rate of the exposed animal. (11) Because liquid aerosols constitute an even more dynamic exposure atmosphere than dry powders, there is need for a better understanding of the process parameters controlling the aerodynamic properties of nebulized aerosols at the point where they actually reach the exposure zone. With this in mind, the aim of the current research was to adapt the Aerogen Pro mesh nebulizer for integrated use within the PreciseInhale platform.…”

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confidence: 99%

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Adapting the Aerogen Mesh Nebulizer for Dried Aerosol Exposures Using the PreciseInhale Platform

Gerde

Nowenwik²,

Sjöberg

et al. 2020

Journal of Aerosol Medicine and Pulmonary Drug Delivery

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Background: Many substances used in inhalation research are water soluble and can be administered as nebulized solutions. Typical examples are therapeutic, small-molecular agents, or macromolecules. Another category is a number of water-soluble agents used for airway diagnostics or disease modeling. Mesh nebulizers have facilitated well-controlled liquid aerosol exposures. Meanwhile, a benchtop inhalation platform, Pre-ciseInhale, was developed for providing small-scale, well-controlled aerosol exposures in preclinical configurations. The purpose of the current research was to adapt the Aerogen mesh nebulizer to work within the PreciseInhale system for both cell culture and rodent exposures. Methods: The wet aerosols produced with the Aerogen Pro nebulizer were dried out in an aerosol holding chamber by supplying dry carrier air, which was provided by passing the incoming ambient air through a column with silica gel. The nebulizer was installed in an aerosol holding chamber between an upstream flowrate pneumotach and a downstream aerosol monitor. By pulsing, the nebulizer output was reduced to 1%-10% of continuous operation to better match the exposure ventilation requirements. Additional drying was obtained by mantling the holding chamber with dried paper. Results and Conclusions: The nebulizer output was reduced to 3-30 lL/min and dried out before reaching the in vitro or in vivo exposure modules. Using solute concentrations in the range of 0.5%-2% (w/w), dried aerosols were produced with a mass median aerodynamic diameter of 1.5-2.0 lm, compared to the 4-5 lm droplets emitted by the nebulizer. Controlling the Aerogen nebulizer under a reduced output scheme within the Pre-ciseInhale platform gave two major advantages: (i) by reducing aerosol output to better match exposure flow rates of single rodents, increased airway deposition yields were obtained in a range of 1%-10% relative to the nebulized amount of test substance and (ii) shrinking aerosol particle sizes through drying improved the peripheral lung deposition of test aerosols.

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Section: Methodsmentioning

confidence: 99%

Section: Fig 1 (A)mentioning

confidence: 99%

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confidence: 99%

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Adapting the Aerogen Mesh Nebulizer for Dried Aerosol Exposures Using the PreciseInhale Platform

Gerde

Nowenwik²,

Sjöberg

et al. 2020

Journal of Aerosol Medicine and Pulmonary Drug Delivery

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“…Dry powder aerosols were generated with the PreciseInhale TM using an impactor nozzle and applying a generation pressure of 30 bar and a reset pressure of 12 bar (Fioni et al 2018).…”

Section: Materials and Aerosol Generationmentioning

confidence: 99%

“…The PreciseInhale TM (Inhalation Sciences Sweden AB, Stockholm, Sweden) aerosol exposure platform was developed to allow small-scale respirable aerosol exposures of different experimental models from in vitro to ex vivo/in vivo lung exposures starting with identical test aerosols. The platform has been used successfully for both air pollution research and the development of pharmaceuticals, as it allows the testing of various exposure modules using the same respirable aerosols (Fioni et al 2018). A direct comparison of results from different modules improves interpretation accuracy and reduces the need for costly crossover studies.…”

Section: Introductionmentioning

confidence: 99%

Respirable aerosol exposures of nicotine dry powder formulations to in vitro, ex vivo, and in vivo pre-clinical models demonstrate consistency of pharmacokinetic profiles

Sciuscio

Hoeng

Peitsch

et al. 2019

Inhalation Toxicology

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Background: Nicotine, because of its volatility, has a complex dosimetry following inhalation as a vapor/aerosol mix. To better control the dosimetry, nicotine could be formulated with a suitable dry powder excipient for use in a clinical inhaler. Aim and Methods: The aim of this study was to investigate the pharmacokinetic PK profile of two dry powder formulations containing 2.5% or 5% nicotine using three experimental models associated to the PreciseInhale TM aerosolization system: the in vitro DissolvIt dissolution system; the ex vivo isolated, ventilated, and perfused lung (IPL) of the rat; and the in vivo intratracheally intubated rat. Results and Discussion: Following exposure, both nicotine formulations had very rapid and similar dissolution and absorption kinetics in both the DissolvIt and IPL exposure models, with an initial halftime of absorption to the single-pass perfusate of 34 and 72 seconds, respectively. In the intratracheally intubated rat, following a rapid initial equilibration between the lungs and systemic compartments, nicotine had a systemic elimination half-time of 2.3-2.4 hours for both formulations. The rapid pulmonary PK of nicotine was likely close to the theoretical equilibration of a low-binding substance with a tissue-blood partition coefficient close to 1. Conclusions: The data generated with the three experimental models provided a comprehensive picture of the inhalation PK of the two nicotine formulations. In particular, the results showed a very rapid dissolution and absorption of the two nicotine formulations and these results could be highly useful for improving the design and calibration of physiologically based PK models to produce more robust predictions.

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Pharmacokinetics of 2-phenoxyethanol and its major metabolite, phenoxyacetic acid, after dermal and inhaled routes of exposure: application to development PBPK model in rats

et al. 2021

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Investigation of Lung Pharmacokinetic of the Novel PDE4 Inhibitor CHF6001 in Preclinical Models: Evaluation of the PreciseInhale Technology

Cited by 25 publications

References 30 publications

Adapting the Aerogen Mesh Nebulizer for Dried Aerosol Exposures Using the PreciseInhale Platform

Adapting the Aerogen Mesh Nebulizer for Dried Aerosol Exposures Using the PreciseInhale Platform

Respirable aerosol exposures of nicotine dry powder formulations to in vitro, ex vivo, and in vivo pre-clinical models demonstrate consistency of pharmacokinetic profiles

Pharmacokinetics of 2-phenoxyethanol and its major metabolite, phenoxyacetic acid, after dermal and inhaled routes of exposure: application to development PBPK model in rats

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